CN108929279A - A kind of fluorine-containing Aminopyrazine class compound and the preparation method and application thereof - Google Patents

A kind of fluorine-containing Aminopyrazine class compound and the preparation method and application thereof Download PDF

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CN108929279A
CN108929279A CN201810845749.4A CN201810845749A CN108929279A CN 108929279 A CN108929279 A CN 108929279A CN 201810845749 A CN201810845749 A CN 201810845749A CN 108929279 A CN108929279 A CN 108929279A
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fluorine
aminopyrazine
class compound
phenyl
substituted
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赵晓明
田亚伟
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Tongji University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The present invention relates to a kind of fluorine-containing Aminopyrazine class compound and the preparation method and application thereof, the chemical structural formulas of fluorine-containing Aminopyrazine class compound are as follows:

Description

A kind of fluorine-containing Aminopyrazine class compound and the preparation method and application thereof
Technical field
The invention belongs to technical field of organic synthesis, be related to a kind of fluorine-containing Aminopyrazine class compound and preparation method thereof with Using.
Background technique
Pyrazine compounds have significant physiological potency, have a wide range of applications in medicine and agricultural chemicals.Example Such as: Te Lapuwei is a kind of drug for treating c-type hepatitis, it belongs to protease inhibitors class antiviral drugs, can pass through resistance Breaking allows the protease of hepatitis C virus duplication to play a role；Bortezomib is used for the treatment of multiple myeloma patients；Method La Wei is the RNA polymerase inhibitor class broad-spectrum antiviral medicament that RNA is relied on, clinical for treating H1N9 and influenza B etc. The patient of relief Ebola virus infection is also used in second phase trial.Referring to document:
[1]Furuta Y,Takahashi K,Shiraki K,Hartman,Amy L,et al.T-705 (favipiravir)and related compounds:Novel broad-spectrum inhibitors of RNAviral infections.Antiviral Res,2009,82(3):95-102.
[2]Caroline AL,Powell D S,Bethel L M,et al.Broad spectrum antiviral activity of favipiravir(T-705):protection from highly lethal inhalational rift valley fever.PLoS Negl.Trop.Dis.,2014,8(4):2790.
[3]Shi F,Li Z,Kong L,et al.Synthesis and crystal structure of 6- fluoro-3-hydroxypyrazine-2-carboxamide.Drug Discov.Ther,2014,8(3):117-120.
[4]Acobson I M,McHutchison J G,Dusheiko G,et al.Telaprevir for previously untreated chronic hepatitis C virus infection.N Engl.J.Med.,2011, 364(25):2405-2416.
Fluorine atom or fluoro-containing group are introduced in drug, the physicochemical characteristics of adjustable Medicine small molecule changes small The pharmacokinetic property of molecule improves the bioavilability and drug metabolism stability of drug.But about pyrazine compounds It is direct it is fluorinated reaction be but rarely reported.Currently, the preparation of fluorine-containing pyrazine compounds is by aromatic nucleophilic fluorine mostly Generation reaction carries out, but needs to carry out pre- function dough, complex steps to reaction substrate, and reaction condition is excessively harsh, not easily-controllable System.Referring to document:
[5]Sarah J.Ryan,Sydonie D.Schimler,Douglas C.Bland,and Melanie S.Sanford.Acyl Azolium Fluorides for Room Temperature Nucleophilic Aromatic Fluorination of Chloro-and Nitroarenes Org.Lett.2015,17(8):1866-1869.
Summary of the invention
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of fluorine-containing Aminopyrazines Class compound and the preparation method and application thereof.
The purpose of the present invention can be achieved through the following technical solutions:
A kind of fluorine-containing Aminopyrazine class compound, the chemical structural formula of the compound are as follows:
Wherein, R is aryl, alkyl or thienyl.
Further, the aryl is phenyl or substituted-phenyl, and the substituted-phenyl includes alkyl-substituted phenyl, halogen One of plain substituted-phenyl, alkoxy substituted phenyl.
Further, the alkyl-substituted phenyl is methyl substituted-phenyl or dimethyl substituted-phenyl, the halogen Substituted-phenyl is chlorine substituted-phenyl, and the alkoxy substituted phenyl is methoxy substitution phenyl.
The carbon atom number of the aryl is 6-8 as a preferred technical solution,.
A kind of preparation method of fluorine-containing Aminopyrazine class compound, this method are as follows: 6- is replaced into -2- Aminopyrazine, Fluorine source And additive is added into organic solvent, arrives the fluorine-containing Aminopyrazine class compound after reaction 10-15h.It synthesizes To product chromatographed through thin-layer chromatography, column or the method for vacuum distillation separates.The method such as chromatographed with thin-layer chromatography, column, institute It is the mixed solvent of nonpolar solvent and polar solvent, preferably solvent with solvent are as follows: count by volume, petroleum ether/acetic acid Ethyl ester=5/1.
Further, it is raw after the 6- substitution -2- Aminopyrazine is reacted by substitution phenyl boric acid with -6 chloropyrazine of 2- amino At.
Further, the substitution phenyl boric acid is that aryl-substituted boric acid, alkyl substituted benzene boric acid or thienyl replace Phenyl boric acid.
Further, the Fluorine source is fluorine reagent, and the additive includes silver carbonate, silver sulfate, palladium acetate or vinegar One of sour copper, the organic solvent include one of acetonitrile, toluene, 1,2- dichloroethanes or dioxane.Fluorine examination Agent (Selectfluor) is bis- (tetrafluoro boric acid) salt of the fluoro- two ring 2.2.2 octane of 1,4- diazotising of 1- chloromethyl -4-.
Further, the molar ratio of the 6- substitution -2- Aminopyrazine, Fluorine source and additive is 3-5:1:0.1-0.3, Preferably 4:1:0.2.
Further, in the reaction process, reaction temperature is 80-90 DEG C, preferably 85 DEG C.
A kind of application of fluorine-containing Aminopyrazine class compound, the fluorine-containing Aminopyrazine class compound is as drug piece Section, in the preparation of drug.
The present invention is catalyzed using the additive (such as silver carbonate) containing transition metal as auxiliary, by fluorine cheap and easy to get Source (Selectfluor) and Aminopyrazine class compound carry out fluorination reaction 12h or so in the organic solvents such as acetonitrile, successfully close At 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound, provides and prepare a variety of substituted 5- fluorine amino pyrroles The method of piperazine compound or 3- fluorine Aminopyrazine compound, and react easy to handle.
Reaction process is as follows:
Wherein, T indicates reaction temperature, and target product is 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class chemical combination Object.
Compared with prior art, the invention has the characteristics that:
1) fluorine-containing Aminopyrazine class compound is in synthesis, first with the phenyl boric acid containing different substituents and 2- ammonia The reaction of -6 chloropyrazine of base generates the Aminopyrazine substrate for containing various substituent groups accordingly, then under the action of additive, control Reaction temperature processed selects suitable solvent, and Aminopyrazine substrate, Selectfluor, additive one kettle way are added in reaction tube, Reaction time control generates final product of the present invention, i.e., fluorine-containing Aminopyrazine class compound, raw material preparation is simply, instead in 12h for the first time Mild condition, wide application range of substrates are answered, and does not need to pre-process substrate, moderate yield (41- may be implemented in reaction 92%) preparation of fluorine-containing Aminopyrazine class compound；
2) fluorine-containing Aminopyrazine class compound prepared by the present invention is important pharmaceutical synthesis segment, can be widely applied to The fields such as chemical machine, chemistry of pesticide and pharmaceutical chemistry.
Specific embodiment
The present invention is described in detail combined with specific embodiments below.The present embodiment is based on the technical solution of the present invention Implemented, the detailed implementation method and specific operation process are given, but protection scope of the present invention be not limited to it is following Embodiment.
Embodiment 1:
With 6- (3,4- 3,5-dimethylphenyl) -2- Aminopyrazine as substrate, the mistake of fluorine-containing Aminopyrazine class compound is prepared Journey is as follows:
In reaction process, it is also possible to other products are generated, such as:
Reaction condition are as follows: 6- (3,4- 3,5-dimethylphenyl) -2- Aminopyrazine (0.40mmol, 4.0 equivalents) is pressed with fluorine reagent Different mol ratio mixing, organic solvent (2.0mL), reaction time 12h, reaction carry out in seal pipe.1.0 are added after reaction to work as The 1- fluoronaphthalene of amount is used as internal standard19F nuclear magnetic resonance measuring yield.Wherein, substrate is indicated with a, and fluorine reagent is indicated with b, 5- fluorine ammonia Base pyrazine compounds indicate that 3- fluorine Aminopyrazine class compound is indicated with c2 with c1,3,5- difluoro Aminopyrazine class compounds It is indicated with c3.
Yield result under different additive, organic solvent, reaction temperature is as shown in the table:
In upper table, DCE 1,2- dichloroethanes, Toluene is toluene, CH3CN is acetonitrile, and Dioxane is dioxane. As can be seen that the 12nd group of reaction effect is best, reaction condition are as follows: Aminopyrazine substrate (0.40mmol, 4.0 equivalents), fluorine Reagent (0.10mmol, 1.0 equivalents), additive A g2CO3(0.02mmol, 20%), organic solvent acetonitrile (2.0mL), reaction temperature 85 DEG C of degree, reaction time 12h.After reaction, the receipts of 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound The sum of rate can reach 92%.
Wherein, the characterization result of 5- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.59 (d, J=1.7Hz, 2H), 7.45 (d, J=2.3Hz, 1H), 7.13- 7.07 (m, 1H), 4.55 (s, 2H), 2.39 (d, J=0.9Hz, 6H)
13C NMR(151MHz,CDCl3): δ 152.32 (d, J=242.7Hz), 152.14 (d, J=2.3Hz), 138.13, 137.95,133.63 (d, J=7.4Hz), 131.54,126.36 (d, J=5.6Hz), 125.02 (d, J=9.6Hz), 21.43.
19F NMR(565MHz,CDCl3):δ-92.34.
IR(KBr):νmax(cm-1)=3372,3319,3193,1640,1547,1423,1398,1373,1286,1180.
HRMS(ESI-TOF)m/z calcd.for C12H13FN3 +[M+H]+:217.1015；found:218.1076.
The characterization result of 3- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.82 (d, J=2.5Hz, 1H), 7.50-7.45 (m, 2H), 7.08-7.04 (m, 1H),4.88(s,2H),2.38(s,6H).
13C NMR(151MHz,CDCl3): δ 147.44 (d, J=248.6Hz), 143.05 (d, J=28.0Hz), (138.46,135.96,130.89,125.99 d, J=7.0Hz), 124.52,21.41.
19F NMR(565MHz,CDCl3):δ-92.28.
IR(KBr):νmax(cm-1)=3478,3180,3299,1630,1605,1376,1267,1192.
HRMS(ESI-TOF)m/z calcd.for C12H13FN3 +[M+H]+:217.1015；found:218.1078.
Under optimum reaction condition in embodiment 1, to Aminopyrazine substrate and corresponding fluorine-containing Aminopyrazine class chemical combination Object is expanded, as a result as shown in embodiment 2-14.Specific operating process are as follows: reaction tube is placed in drying in baking oven, later It takes out and is cooled to room temperature；Respectively weigh 0.4mmol Aminopyrazine substrate, 0.1mmol fluorine reagent (Selectfluor) and 0.02mmol silver carbonate, one kettle way are added in reaction tube, and 1-2mL is added and analyzes pure acetonitrile, and capping pipe is placed in 85 DEG C 12h or so is reacted in oil bath.After reaction, acetonitrile is fallen in vacuum distillation, and residue is through the isolated target product of thin-layer chromatography (solvent are as follows: petrol ether/ethyl acetate=5:1, v/v).
Embodiment 2:
5- fluorine Aminopyrazine class compound are as follows:
3- fluorine Aminopyrazine class compound are as follows:
The sum of yield of 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound is 90%.
Wherein, the characterization result of 5- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.78 (s, 1H), 7.73 (d, J=7.8Hz, 1H), 7.43 (d, J=2.3Hz, 1H), 4.52 (s, 2H), 2.33 (d, J=11.7Hz, 6H)
13C NMR(151MHz,CDCl3): δ 152.27 (d, J=242.7Hz), 152.08 (d, J=2.5Hz), 138.76, 137.90 (d, J=26.0Hz), 136.86,131.30 (d, J=7.7Hz), 129.86,129.59 (d, J=5.5Hz), 126.12 (d, J=6.9Hz), 124.66 (d, J=9.6Hz), 19.93,19.76.
19F NMR(565MHz,CDCl3):δ-92.16.
IR(KBr):νmax(cm-1)=3195,2922,1636,1547,1464,1423,1286,1271,1209.
HRMS(ESI-TOF)m/z calcd.for C12H13FN3 +[M+H]+:217.1015；found:218.1105.
The characterization result of 3- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.82 (d, J=2.5Hz, 1H), 7.68-7.63 (m, 1H), 7.59 (dd, J= 7.8,2.0Hz, 1H), 4.88 (s, 2H), 2.32 (d, J=14.6Hz, 7H)
13C NMR(151MHz,CDCl3): δ 148.48 (d, J=4.8Hz), 147.32 (d, J=248.2Hz), 143.12, (138.00,137.17,133.61,130.14,127.79,125.64 d, J=6.8Hz), 124.05,19.97,19.69.
19F NMR(565MHz,CDCl3):δ-92.65.
IR(KBr):νmax(cm-1)=3179,2918,1624,1473,1385,1226,1201,1177.
HRMS(ESI-TOF)m/z calcd.for C12H13FN3 +[M+H]+:217.1015；found:218.1121.
Embodiment 3:
5- fluorine Aminopyrazine class compound are as follows:
3- fluorine Aminopyrazine class compound are as follows:
The sum of yield of 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound is 88%.
Wherein, the characterization result of 5- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.54 (d, J=2.2Hz, 1H), 7.38-7.34 (m, 2H), 7.30 (d, J= 7.5Hz, 2H), 4.56 (s, 2H), 2.30 (d, J=1.2Hz, 3H)
13C NMR(151MHz,CDCl3): δ 152.23 (d, J=239.7Hz), 152.14 (d, J=2.4Hz), 139.73, (139.52,136.68,133.45 d, J=6.0Hz), 130.58,129.62,129.36,126.20-125.53 (m), 19.63 (d, J=3.3Hz)
19F NMR(565MHz,CDCl3):δ-93.40.
IR(KBr):νmax(cm-1)=3324,3196,1621,1541,1437,1404,1271,1194,1035.
HRMS(ESI-TOF)m/z calcd.for C11H11FN3 +[M+H]+:203.0859；found:204.0944.
The characterization result of 3- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.53 (d, J=2.5Hz, 1H), 7.35 (dd, J=7.4,1.5Hz, 1H), 7.34–7.30(m,1H),7.30–7.27(m,2H),5.00–4.83(m,2H),2.37(s,3H).
13C NMR(151MHz,CDCl3): δ 150.47 (d, J=4.9Hz), 146.99 (d, J=248.7Hz), 142.98, 142.79,136.31 (d, J=1.7Hz), 136.14,130.88,129.52,128.83,128.66 (d, J=6.6Hz), 20.27.
19F NMR(565MHz,CDCl3):δ-91.84.
IR(KBr):νmax(cm-1)=3318,3177,1627,1540,1467,1380,1316,1192,
HRMS(ESI-TOF)m/z calcd.for C11H11FN3 +[M+H]+:203.0859；found:204.0952.
Embodiment 4:
5- fluorine Aminopyrazine class compound are as follows:
3- fluorine Aminopyrazine class compound are as follows:
The sum of yield of 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound is 90%.
Wherein, the characterization result of 5- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.82-7.76 (m, 2H), 7.47 (d, J=2.3Hz, 1H), 7.37 (t, J= 7.7Hz,1H),7.29–7.24(m,1H),4.55(s,2H),2.43(s,3H).
13C NMR(151MHz,CDCl3): δ 152.35 (d, J=242.8Hz), 152.14 (d, J=2.5Hz), 138.26, 137.82 (d, J=26.1Hz), 133.67 (d, J=7.7Hz), 130.61,129.16 (d, J=5.4Hz), 128.47, 125.78 (d, J=6.6Hz), 125.15 (d, J=9.5Hz), 21.55.
19F NMR(565MHz,CDCl3):δ-94.94.
IR(KBr):νmax(cm-1)=3335,1668,1617,1544,1458,1419,1399,1267,1207.
HRMS(ESI-TOF)m/z calcd.for C11H11FN3 +[M+H]+:203.0859；found:204.0936.
The characterization result of 3- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.84 (d, J=2.5Hz, 1H), 7.69 (s, 1H), 7.65 (d, J=7.8Hz, 1H), 7.35 (t, J=7.6Hz, 1H), 7.24 (d, J=7.7Hz, 0H), 4.86 (s, 2H), 2.43 (s, 3H)
13C NMR(151MHz,CDCl3): δ 148.45 (d, J=4.9Hz), 147.48 (d, J=248.7Hz), 143.08 (d, J=28.3Hz), 138.57,135.98,129.98,128.76,127.36,125.97 (d, J=6.7Hz), 123.78, 21.54.
19F NMR(565MHz,CDCl3):δ-92.13.
IR(KBr):νmax(cm-1)=3503,3318,3178,1627,1489,1477,1219,1190.
HRMS(ESI-TOF)m/z calcd.for C11H11FN3 +[M+H]+:203.0859；found:204.0927.
Embodiment 5:
5- fluorine Aminopyrazine class compound are as follows:
3- fluorine Aminopyrazine class compound are as follows:
The sum of yield of 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound is 87%.
Wherein, the characterization result of 5- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.95-7.87 (m, 1H), 7.44 (d, J=2.3Hz, 0H), 7.29 (d, J= 8.0Hz,1H),4.53(s,1H),2.41(s,1H).
13C NMR(151MHz,CDCl3): δ 152.26 (d, J=242.7Hz), 152.10 (d, J=2.3Hz), 140.03, 137.69 (d, J=25.9Hz), 130.93 (d, J=7.7Hz), 129.32,128.51 (d, J=6.3Hz), 124.79 (d, J= 9.5Hz),21.42.
9F NMR(565MHz,CDCl3):δ-92.27.
IR(KBr):νmax(cm-1)=3382,3307,3197,1634,1542,1462,1409,1273,1201
HRMS(ESI-TOF)m/z calcd.for C11H11FN3 +[M+H]+:203.0859；found:204.0954.
The characterization result of 3- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.83 (d, J=2.5Hz, 1H), 7.76 (d, J=8.0Hz, 2H), 7.26 (d, J =2.6Hz, 2H), 4.87 (s, 2H), 2.40 (s, 3H)
13C NMR(151MHz,CDCl3): δ 148.32 (d, J=4.9Hz), 147.35 (d, J=248.3Hz), 143.04 (d, J=28.1Hz), 139.27,133.22,129.57,126.52,125.59 (d, J=6.9Hz), 21.31.
19F NMR(565MHz,CDCl3):δ-92.52.
IR(KBr):νmax(cm-1)=3504,3301,3179,1646,1628,1489,1466,1215,1195.3195
HRMS(ESI-TOF)m/z calcd.for C11H11FN3 +[M+H]+:203.0859；found:204.0924.
Embodiment 6:
5- fluorine Aminopyrazine class compound are as follows:
3- fluorine Aminopyrazine class compound are as follows:
The sum of yield of 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound is 85%.
Wherein, the characterization result of 5- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.52 (d, J=2.1Hz, 1H), 7.46-7.38 (m, 2H), 7.07 (td, J= 7.5,1.0Hz, 1H), 7.00 (dd, J=8.3,0.9Hz, 1H), 4.52 (s, 2H), 3.84 (s, 3H)
13C NMR(151MHz,CDCl3): δ 157.26,152.76 (d, J=241.2Hz), 152.18 (d, J=2.5Hz), 137.39 (d, J=32.2Hz), 130.99,130.80,125.45 (d, J=9.3Hz), 123.55 (d, J=6.3Hz), 120.80,111.31,55.75.
19F NMR(565MHz,CDCl3):δ-91.59.
IR(KBr):νmax(cm-1)=3316,3194,1628,1603,1542,1459,1448,1407,1280,1022.
HRMS(ESI-TOF)m/z calcd.for C11H10FN3O+[M+H]+:219.0808；found:220.0850.
The characterization result of 3- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 8.00 (d, J=2.4Hz, 1H), 7.70 (dd, J=7.7,1.8Hz, 1H), 7.38 (t, J=7.9Hz, 1H), 7.06 (t, J=7.5Hz, 1H), 7.00 (d, J=8.3Hz, 1H), 4.85 (s, 3H), 3.87 (s,4H).
13C NMR(151MHz,CDCl3): δ 156.98,147.06 (d, J=248.2Hz), 146.39 (d, J=4.9Hz), 143.04 (d, J=28.5Hz), 130.81,130.32,130.27,125.30,120.99,111.39,55.59.
19F NMR(565MHz,CDCl3):δ-92.68.
IR(KBr):νmax(cm-1)=3320,3200,1633,1610,1552,1463,1413,1295,1026.
HRMS(ESI-TOF)m/z calcd.for C11H10FN3O+[M+H]+:219.0808；found:190.0863.
Embodiment 7:
5- fluorine Aminopyrazine class compound are as follows:
3- fluorine Aminopyrazine class compound are as follows:
The sum of yield of 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound is 87%.
Wherein, the characterization result of 5- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.60 (dt, J=7.8,1.3Hz, 1H), 7.56 (dt, J=2.6,1.2Hz, 1H), 7.48 (d, J=2.3Hz, 1H), 7.00 (ddd, J=8.3,2.6,0.9Hz, 1H), 3.88 (s, 4H)
13C NMR(151MHz,CDCl3): δ 159.71,152.31 (d, J=243.0Hz), 152.11 (d, J=2.3Hz), 137.30 (d, J=25.5Hz), 135.03 (d, J=7.8Hz), 129.60,125.44 (d, J=9.5Hz), 121.12 (d, J= 7.2Hz), 115.86,113.70 (d, J=5.6Hz), 55.40.
19F NMR(565MHz,CDCl3):δ-92.00.
IR(KBr):νmax(cm-1)=3435,3343,2919,1644,1545,1473,1419,1401,1268,1248.
HRMS(ESI-TOF)m/z calcd.for C11H10FN3O+[M+H]+:219.0808；found:220.0847.
The characterization result of 3- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.85 (d, J=2.5Hz, 1H), 7.47-7.41 (m, 2H), 7.37 (t, J= 8.0Hz,1H),4.89(s,2H),3.88(s,3H).
13C NMR(151MHz,CDCl3): δ 160.03,148.02 (d, J=4.8Hz), 147.54 (d, J=249.2Hz), 143.08 (d, J=28.2Hz), 137.42,129.90,126.02 (d, J=7.1Hz), 118.98,115.01,112.04, 55.40.
19F NMR(565MHz,CDCl3):δ-91.71.
IR(KBr):νmax(cm-1)=3330,3192,2925,1627,1600,1422,1308,1198,1179.
HRMS(ESI-TOF)m/z calcd.for C11H10FN3O+[M+H]+:219.0808；found:220.0841.
Embodiment 8:
5- fluorine Aminopyrazine class compound are as follows:
3- fluorine Aminopyrazine class compound are as follows:
The sum of yield of 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound is 93%.
Wherein, the characterization result of 5- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 8.03-7.96 (m, 2H), 7.40 (d, J=2.4Hz, 1H), 7.03-6.97 (m, 2H),4.53(s,2H),3.87(s,3H).
13C NMR(151MHz,CDCl3): δ 160.90,152.06 (d, J=2.4Hz), 152.03 (d, J=242.3Hz), 137.38 (d, J=25.9Hz), 130.12 (d, J=7.0Hz), 126.22 (d, J=7.9Hz), 124.21 (d, J=9.5Hz), 113.99,55.38.
19F NMR(565MHz,CDCl3):δ-92.18.
IR(KBr):νmax(cm-1)=3454,3357,2920,2850,1608,1448,1406,1246,1209,1180.
HRMS(ESI-TOF)m/z calcd.for C11H10FN3O+[M+H]+:219.0808；found:220.0851.
The characterization result of 3- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.84-7.81 (m, 1H), 7.80 (d, J=2.6Hz, 0H), 7.01-6.95 (m, 1H),4.84(s,1H),3.86(s,2H).
13C NMR(151MHz,CDCl3): δ 160.54,148.05 (d, J=4.5Hz), 147.12 (d, J=247.8Hz), 142.94 (d, J=28.3Hz), 128.60,127.97,125.13 (d, J=6.9Hz), 114.23,55.40.
19F NMR(565MHz,CDCl3):δ-93.16.
IR(KBr):νmax(cm-1)=3503,3169,2921,1632,1471,1251,1212,1173.
HRMS(ESI-TOF)m/z calcd.for C11H10FN3O+[M+H]+:219.0808；found:220.0847.
Embodiment 9:
5- fluorine Aminopyrazine class compound are as follows:
3- fluorine Aminopyrazine class compound are as follows:
The sum of yield of 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound is 87%.
Wherein, the characterization result of 5- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3):δ8.02–7.98(m,1H),7.51–7.43(m,2H),4.55(s,1H).
13C NMR(151MHz,CDCl3): δ 152.30 (d, J=242.6Hz), 152.28 (d, J=2.2Hz), 137.53 (d, J=26.1Hz), 133.74 (d, J=7.7Hz), 129.82,128.64,128.59,125.36 (d, J=9.5Hz)
19F NMR(565MHz,CDCl3):δ-92.51.
IR(KBr):νmax(cm-1)=3478,3372,2921,1614,1551,1464,1427,1406,1268,1027.
HRMS(ESI-TOF)m/z calcd.for C12H13FN3 +[M+H]+:189.0702；found:190.0799.
The characterization result of 3- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3):δ7.91–7.84(m,1H),7.51–7.39(m,1H),4.91(s,1H).
13C NMR(151MHz,CDCl3): δ 148.27 (d, J=4.8Hz), 147.51 (d, J=249.0Hz), 143.16 (d, J=28.2Hz), 136.01,129.22,128.87,126.67,125.88 (d, J=7.0Hz)
19F NMR(565MHz,CDCl3):δ-91.92.
IR(KBr):νmax(cm-1)=3486,3377,2930,1621,1555,1466,1432,1270,1032.
HRMS(ESI-TOF)m/z calcd.for C12H13FN3 +[M+H]+:189.0702；found:190.0808.
Embodiment 10:
5- fluorine Aminopyrazine class compound are as follows:
3- fluorine Aminopyrazine class compound are as follows:
The sum of yield of 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound is 68%.
Wherein, the characterization result of 5- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3) δ 8.03 (d, J=2.4Hz, 1H), 7.94-7.88 (m, 1H), 7.50 (d, J= 2.3Hz,1H),7.43–7.38(m,2H),4.60(s,3H).
13C NMR(151MHz,CDCl3) δ 152.29 (d, J=243.1Hz), 152.18 (d, J=2.6Hz), 135.91, 135.74,135.47 (d, J=7.8Hz), 134.66,129.79,128.62 (d, J=5.9Hz), 126.71 (d, J= 7.7Hz), 126.11 (d, J=9.6Hz)
19F NMR(565MHz,CDCl3)δ-92.10.
IR(KBr):νmax(cm-1)=3457,3312,3200,1549,1633,1466,1405,1263,1204.
HRMS(ESI-TOF)m/z calcd.for C11H10ClFN3O+[M+H]+:223.0313；found:224.0878.
The characterization result of 3- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.90 (q, J=1.4Hz, 1H), 7.85 (d, J=2.5Hz, 1H), 7.76- 7.72(m,1H),4.90(s,3H).
13C NMR(151MHz,CDCl3): δ 147.72 (d, J=250.2Hz), 146.71 (d, J=4.9Hz), 143.15, (137.77,134.96,130.04,129.17,126.87,125.91 d, J=7.3Hz), 124.58.
19F NMR(565MHz,CDCl3):δ-90.80.
IR(KBr):νmax(cm-1)=3506,3299,9181,1626,1490,1466,1395,1211,1194.
HRMS(ESI-TOF)m/z calcd.for C11H10ClFN3O+[M+H]+:223.0313；found:224.073.
Embodiment 11:
5- fluorine Aminopyrazine class compound are as follows:
3- fluorine Aminopyrazine class compound are as follows:
The sum of yield of 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound is 69%.
Wherein, the characterization result of 5- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.98 (d, J=8.3Hz, 1H), 7.49 (d, J=2.2Hz, 0H), 7.45 (d, J =8.3Hz, 1H), 4.57 (s, 1H)
13C NMR(151MHz,CDCl3): δ 152.22 (d, J=242.8Hz), 152.14 (d, J=2.6Hz), 136.21 (d, J=25.8Hz), 135.96,132.16 (d, J=7.9Hz), 129.92 (d, J=6.9Hz), 128.81,125.71 (d, J =9.8Hz)
19F NMR(565MHz,CDCl3):δ-92.03.
IR(KBr):νmax(cm-1)=3470,3170,1627,1470,1399,1264,1217.
HRMS(ESI-TOF)m/z calcd.for C11H10ClFN3O+[M+H]+:223.0313；found:224.0836.
The characterization result of 3- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3):δ7.86–7.79(m,1H),7.46–7.39(m,1H),4.88(s,1H).
13C NMR(151MHz,CDCl3): δ 147.57 (d, J=249.5Hz), 147.03 (d, J=4.7Hz), 143.18 (d, J=28.3Hz), 135.3,134.45,129.03,127.88,125.66 (d, J=7.1Hz)
19F NMR(565MHz,CDCl3):δ-91.32.
IR(KBr):νmax(cm-1)=3480,3173,1613,1547,1455,1406,1264,1205.
HRMS(ESI-TOF)m/z calcd.for C11H10ClFN3O+[M+H]+:223.0313；found:224.0835.
Embodiment 12:
5- fluorine Aminopyrazine class compound are as follows:
3- fluorine Aminopyrazine class compound are as follows:
The sum of yield of 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound is 57%.
Wherein, the characterization result of 5- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 8.17 (d, J=2.1Hz, 1H), 7.91-7.87 (m, 1H), 7.56-7.50 (m, 2H),4.60(s,2H).
13C NMR(151MHz,CDCl3): δ 152.22 (d, J=243.1Hz), 152.15 (d, J=2.4Hz), 134.73 (d, J=25.6Hz), 134.03,133.62 (d, J=8.3Hz), 132.97,130.52,130.40 (d, J=6.6Hz), 127.69 (d, J=8.2Hz), 126.41 (d, J=9.8Hz)
19F NMR(565MHz,CDCl3):δ-91.60.
IR(KBr):νmax(cm-1)=3483,3355,1621,1544,1453,1401,1378,1263,1204.
HRMS(ESI-TOF)m/z calcd.for C11H10Cl2FN3O+[M+H]+:256.9923；found:257.9987.
The characterization result of 3- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 8.01 (d, J=2.1Hz, 1H), 7.84 (d, J=2.5Hz, 1H), 7.71 (dd, J=8.4,2.1Hz, 1H), 7.52 (d, J=8.4Hz, 1H), 4.92 (s, 2H)
13C NMR(151MHz,CDCl3): δ 147.75 (d, J=250.5Hz), 145.69 (d, J=4.6Hz), 143.29 (d, J=28.2Hz), 135.90,133.39,133.21,130.75,128.56,125.70 (d, J=7.2Hz), 125.55.
19F NMR(565MHz,CDCl3):δ-90.29.
IR(KBr):νmax(cm-1)=3487,3335,1624,1471,1428,1373,1298,1207,1139,1028.
HRMS(ESI-TOF)m/z calcd.for C11H10Cl2FN3O+[M+H]+:256.9923；found:257.9995.
Embodiment 13:
5- fluorine Aminopyrazine class compound are as follows:
3- fluorine Aminopyrazine class compound are as follows:
The sum of yield of 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound is 58%.
Wherein, the characterization result of 5- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.75 (t, J=2.8Hz, 1H), 7.42 (d, J=5.0Hz, 1H), 7.30 (d, J =2.3Hz, 1H), 7.09 (t, J=4.4Hz, 1H), 4.47 (s, 2H)
13C NMR(151MHz,CDCl3): δ 151.97,150.32 (d, J=243.0Hz), 147.00 (d, J= 10.7Hz), 144.79,129.58 (d, J=28.0Hz), 124.22 (d, J=9.6Hz), 114.39 (d, J=12.5Hz), 112.36 (d, J=2.1Hz)
19F NMR(565MHz,CDCl3):δ-90.32.
IR(KBr):νmax(cm-1)=3479,3337,3216,1614,1544,1527,1451,1440,1278,1210.
HRMS(ESI-TOF)m/z calcd.for C8H6FN3S+[M+H]+:195.0266；found:196.0363.
The characterization result of 3- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3): δ 7.73 (d, J=2.5Hz, 1H), 7.45 (d, J=3.6Hz, 1H), 7.32 (d, J =5.0Hz, 1H), 7.03 (t, J=4.4Hz, 1H), 4.83 (s, 2H)
13C NMR(151MHz,CDCl3): 146.92 (d, J=248.6Hz), 143.78 (d, J=4.8Hz), 143.03 (d, J=28.7Hz), 140.61,128.18,127.61,124.86,124.12 (d, J=7.2Hz)
19F NMR(565MHz,CDCl3):δ-91.65.
IR(KBr):νmax(cm-1)=3455,3295,3174,1632,1536,1477,1444,1317,1292,1196.
HRMS(ESI-TOF)m/z calcd.for C8H6FN3S+[M+H]+:195.0266；found:19.0339.
Embodiment 14:
5- fluorine Aminopyrazine class compound are as follows:
3- fluorine Aminopyrazine class compound are as follows:
The sum of yield of 5- fluorine Aminopyrazine class compound and 3- fluorine Aminopyrazine class compound is 41%.
Wherein, the characterization result of 5- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3):δ7.27(s,1H),4.36(s,3H),2.33(s,2H).
13C NMR(151MHz,CDCl3): δ 153.29 (d, J=238.6Hz), 152.01 (d, J=2.5Hz), 138.67 (d, J=32.4Hz), 123.86 (d, J=9.2Hz), 17.66 (d, J=5.4Hz)
19F NMR(565MHz,CDCl3):δ-96.35.
IR(KBr):νmax(cm-1)=3440,3311,3202,1637,1540,1471,1214,1386,1270,1208, 1159.
HRMS(ESI-TOF)m/z calcd.for C5H6FN3 +[M+H]+:127.0546；found:128.0619.
The characterization result of 3- fluorine Aminopyrazine class compound are as follows:
1H NMR(600MHz,CDCl3):δ7.22–7.19(m,1H),4.79(s,2H),2.28(s,3H).
13C NMR(151MHz,CDCl3): δ 148.23 (d, J=4.9Hz), 146.8 (d, J=246.0Hz), 143.0 (d, ), J=28.4Hz 127.5 (d, J=6.6Hz), 20.2 (d, J=2.7Hz)
19F NMR(565MHz,CDCl3):δ-93.77.
IR(KBr):νmax(cm-1)=3386,3312,3140,2919,2849,1650,1470,1431,1307,1285, 1184.
HRMS(ESI-TOF)m/z calcd.for C5H7FN3 +[M+H]+:128.0624；found:128.0623.
Embodiment 15:
According to embodiment 1-14, the R in following chemical structural formula is replaced with as different aryl, alkyl or thienyl, Different fluorine-containing Aminopyrazine class compounds can be obtained, these fluorine-containing Aminopyrazine class compounds can be used as drug segment, use In the preparation of drug.
Wherein, aryl is phenyl or substituted-phenyl, and substituted-phenyl includes alkyl-substituted phenyl, halogen substituted phenyl, alcoxyl One of base substituted-phenyl.
Preferably, alkyl-substituted phenyl is methyl substituted-phenyl or dimethyl substituted-phenyl, halogen substituted phenyl is chlorine Substituted-phenyl, alkoxy substituted phenyl are methoxy substitution phenyl.
Embodiment 16:
For the fluorine-containing Aminopyrazine class compound in embodiment 15 the preparation method comprises the following steps: by 6- replace -2- Aminopyrazine, Fluorine source and additive are added into organic solvent, are reacted after 10-15h at 80-90 DEG C to get to corresponding fluorine-containing Aminopyrazine Class compound.
Wherein, 6- substitution -2- Aminopyrazine generates after being reacted by substitution phenyl boric acid with -6 chloropyrazine of 2- amino.Substituted benzene boron Acid group is chosen as aryl-substituted boric acid, alkyl substituted benzene boric acid or thienyl substituted benzene boron according to the required difference for generating product Acid.Fluorine source is fluorine reagent, and additive is silver carbonate, silver sulfate, palladium acetate or copper acetate, and organic solvent is acetonitrile, toluene, 1,2- Dichloroethanes or dioxane.The molar ratio of 6- substitution -2- Aminopyrazine, Fluorine source and additive is 3-5:1:0.1-0.3.
The above description of the embodiments is intended to facilitate ordinary skill in the art to understand and use the invention. Person skilled in the art obviously easily can make various modifications to these embodiments, and described herein general Principle is applied in other embodiments without having to go through creative labor.Therefore, the present invention is not limited to the above embodiments, ability Field technique personnel announcement according to the present invention, improvement and modification made without departing from the scope of the present invention all should be of the invention Within protection scope.

Claims (10)

1. a kind of fluorine-containing Aminopyrazine class compound, which is characterized in that the chemical structural formula of the compound are as follows:
Wherein, R is aryl, alkyl or thienyl.
2. a kind of fluorine-containing Aminopyrazine class compound according to claim 1, which is characterized in that the aryl is phenyl Or substituted-phenyl, the substituted-phenyl include alkyl-substituted phenyl, halogen substituted phenyl, one in alkoxy substituted phenyl Kind.
3. a kind of fluorine-containing Aminopyrazine class compound according to claim 2, which is characterized in that the alkyl substituted benzene Base is methyl substituted-phenyl or dimethyl substituted-phenyl, and the halogen substituted phenyl is chlorine substituted-phenyl, the alkoxy Substituted-phenyl is methoxy substitution phenyl.
4. a kind of preparation method of fluorine-containing Aminopyrazine class compound as described in any one of claims 1 to 3, feature exist In this method are as follows: replace -2- Aminopyrazine, Fluorine source and additive to be added into organic solvent 6-, after reacting 10-15h, i.e., Obtain the fluorine-containing Aminopyrazine class compound.
5. a kind of preparation method of fluorine-containing Aminopyrazine class compound according to claim 4, which is characterized in that described 6- substitution -2- Aminopyrazine generates after being reacted by substitution phenyl boric acid with -6 chloropyrazine of 2- amino.
6. a kind of preparation method of fluorine-containing Aminopyrazine class compound according to claim 5, which is characterized in that described Substitution phenyl boric acid is that aryl-substituted boric acid, alkyl substituted benzene boric acid or thienyl replace phenyl boric acid.
7. a kind of preparation method of fluorine-containing Aminopyrazine class compound according to claim 4, which is characterized in that described Fluorine source is fluorine reagent, and the additive includes one of silver carbonate, silver sulfate, palladium acetate or copper acetate, and described is organic Solvent includes one of acetonitrile, toluene, 1,2- dichloroethanes or dioxane.
8. a kind of preparation method of fluorine-containing Aminopyrazine class compound according to claim 4, which is characterized in that described The molar ratio of 6- substitution -2- Aminopyrazine, Fluorine source and additive is 3-5:1:0.1-0.3.
9. a kind of preparation method of fluorine-containing Aminopyrazine class compound according to claim 4, which is characterized in that described In reaction process, reaction temperature is 80-90 DEG C.
10. a kind of application of fluorine-containing Aminopyrazine class compound as described in any one of claims 1 to 3, which is characterized in that institute The fluorine-containing Aminopyrazine class compound stated is as drug segment, in the preparation of drug.
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